Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that affects approximately 0.4 million people in the US and more than 2 million worldwide. Memory T cells specific for components of the myelin sheath appear to be crucial for the pathogenesis of MS. With the voltage-gated potassium channel Kv1.3 we have recently identified an exciting new molecular target that allows selective pharmacological suppression of effector memory T (TEM) cells. Expression of this channel is increased in both CD4+ and CD8+ TEM cells and Kv1.3 blockers have been shown to potently suppress their proliferation without impairing the function of naive and central memory T cells. We have further validated Kv1.3 as a new therapeutic target for MS by demonstrating that myelin-reactive T cells from patients with MS are predominantly Kv1.3-high TEM cells and that the Kv1.3 blocking peptide ShK can treat EAE in rats. Despite Kv1.3's obvious therapeutic importance, specific and potent small molecule inhibitors of Kv1.3 have so far not been developed by the pharmaceutical industry. Following up on anecdotal reports from the late 1980s that tea prepared from Ruta graveolens, the common rue, had beneficial effects in MS, we discovered that Ruta contained a small molecule called 5-methoxypsoralen (5-MOP), which blocks Kv1.3 in the micromolar range. Using 5-MOP as a template we started a medicinal chemistry effort and have since then improved the potency of the alkoxypsoralens into the low nanomolar range and proposed an essential pharmacophore for small molecule Kv1.3 blockers. Our most potent compound so far is PAP-1, which inhibits Kv1.3 with a Kd of 2 nM and displays 22-fold selectivity over the cardiac K+ channel Kv1.5. Under Aim-1 of this proposal we intend to further explore the structure-activity relationship (SAR) around our pharmacophore model in order to further improve the potency and selectivity of our compounds. Under Aim-2 we will then test the best new compounds in adoptive-transfer EAE, an animal model of MS. The overall goal of this proposal is to obtain an ideal small molecule Kv1.3 blocker for pre-clinical development as a new drug candidate for MS. Lay: In multiple sclerosis the immune system attacks proteins in the brain of afflicted patients. The aim of this study is to identify and test new drugs that can suppress the white blood cells that are invading the brain.